Parkinson's disease (PD) is progressive neurodegenerative disorder. A combination of medical and surgical treatments has improved the quality of the lives of most PD patients. But the relentless progression of degeneration of the substantia nigra and consequent loss of dopamine in the basal ganglia ultimately leads to a severe debilitating state. Efforts to slow the disease even to a small degree will extend the life span and improve the quality of a patient's life and reduce the national burden of cost of care of PD patients. At present there are no drugs that can slow the progression of the disease. In this proposal it is hypothesized, that among all the available compounds, nicotine shows significant promise to be a neuroprotective agent for the degenerating dopaminergic neurons in PD. We will discuss evidence to support that: 1. Nicotine is neuroprotective in several models of neurotoxicity, 2. The neuroprotective effects of nicotine are mediated via several well established cell survival and anti-apoptotic molecular cascades, 3. The degenerating dopaminergic neurons in PD do show evidence of apoptotic death, 4. Nicotine is neuroprotective in animal models of PD, and 5. Nicotine's neuroprotective actions are accomplished by the activation of PI3K/Akt antiapoptotic pathways byalpha4 - beta2 andalpha? - beta2 nicotinic receptors, which areabundant inthesubstantia nigra and striatum. A tentative research plan to conduct clinical trial using Transdermal nicotine patches is also proposed.